The goal of the proposed research is to understand the mechanisms involved in the phenomena of neurotransmitter receptor supersensitivity and neurotransmitter receptor desensitization. More specifically, the proposed research is designed to explore these phenomena with respect to histamine H1 and muscarinic acetylcholine receptors, two receptors which are present in the CNS and are competitively antagonized by a large number of psychotherapeutic drugs. Many of these drugs caused receptor sensitivity changes in brain. A clone of mouse neuroblastoma (NIE-115) with histamine H1 and muscular acetylcholine receptors which mediate cyclic GMP synthesis, fetal rat brain cells in aggregating culture, and rat brain in vivo will be studied. Receptor sensitivity changes will be determined by studying the changes in the ability of cells: 1) to respond to receptor activation (cyclic GMP synthesis) and/or 2) bind radioactively labeled antagonists of histamine H1 and muscarinic acetylcholine receptors. By chronic infusion of cholinergic agonists into the corpus striatum of rat, alterations in receptor sensitivity will be determined in vivo and correlated with behavioral changes in the animals. Desensitization of muscarinic acetylcholine receptors in the striatum may be involved in the pathophysiology of Tardive Dyskinesia in some patients.